Cytochromes P450 (CYTP450) are now recognized as one of three primary branches of the biomedically important arachidonate cascade together with the canonical cyclooxygenases and lipoxidases. The oxidative metabolites from these pathways are also subject to further enzymatic and non- enzymatic transformations resulting in a rich spectrum of bioactive products. Over the past decade, this and other laboratories have cogently demonstrated the relevance of the CYT P450 cascade to renal physiology. In particular, metabolites from the epoxygenase and omega-hydroxylase pathways have been implicated in vasoreactivity, ion and water transport, hormonal signaling, and experimental hypertension. To expedite current investigation of the biogenesis, regulation, and disposition of these eicosanoids in the kidney and their role in renal function, this project proposes to: (1) Prepare and evaluate differential and specific CYTP450 arachidonate epoxygenase and omega-hydroxylase inhibitors; (2) Generate renal eicosanoid analogs with modified activity and/or stability; (3) Devise efficient, asymmetric syntheses of bioactive renal eicosanoids suitable for investigational-scale studies.
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